Synthesis of optically active heterocyclic compounds via deracemization of 1,2-diol monotosylate derivatives bearing a long aliphatic chain by a combination of enzymatic hydrolysis with Mitsunobu inversion

Article abstract of DOI:10.1016/j.tetasy.2012.11.023

We have succeeded in accomplishing the deracemization of (±)-2-acetoxydecyl and (±)-acetoxy-6-benzyloxyhexyl tosylates, which have a long substituent, via an enzyme-mediated enantioselective hydrolysis with a Mitsunobu inversion using polymer-supported triphenylphosphine to afford the corresponding (S)-enantiomer. Enantiomerically pure (S)- and (R)-γ-dodecalactones, a fruit flavor, were synthesized from (S)-2-acetoxydecyl tosylate as the mutual starting material. The poisonous alkaloid (S)-coniine was also synthesized using enantiomerically pure allyl amine as the key intermediate derived from (S)-acetoxy-6-benzyloxyhexyl tosylate.

Full text of DOI:10.1016/j.tetasy.2012.11.023

Tetrahedron: Asymmetry 24 (2013) 108–115
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Synthesis of optically active heterocyclic compounds via deracemization
of 1,2-diol monotosylate derivatives bearing a long aliphatic chain by a
combination of enzymatic hydrolysis with Mitsunobu inversion
⇑
Kazutsugu Matsumoto , Kazumasa Usuda, Hirokazu Okabe, Manabu Hashimoto, Yasutaka Shimada
Department of Chemistry and Life Science, Meisei University, 2-1-1 Hodokubo, Hino, Tokyo 191-8506, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 November 2012
Accepted 26 November 2012
We have succeeded in accomplishing the deracemization of ( )-2-acetoxydecyl and ( )-acetoxy-6-ben-
zyloxyhexyl tosylates, which have a long substituent, via an enzyme-mediated enantioselective hydroly-
sis with a Mitsunobu inversion using polymer-supported triphenylphosphine to afford the corresponding
(S)-enantiomer. Enantiomerically pure (S)- and (R)-c-dodecalactones, a fruit flavor, were synthesized
from (S)-2-acetoxydecyl tosylate as the mutual starting material. The poisonous alkaloid (S)-coniine
was also synthesized using enantiomerically pure allyl amine as the key intermediate derived from
(S)-acetoxy-6-benzyloxyhexyl tosylate.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
For kinetic resolution methodology, the maximum theoretical
yield is limited to 50% for each enantiomer; this drawback is a bot-
Optically active 1,2-diol monotosylates are useful intermediates
for chiral non-racemic epoxides, amino alcohols, alkyl carbinols,
and so on, during the synthesis of natural and biologically active
compounds. The hydrolase-mediated kinetic resolution of racemic
1,2-diol monotosylate derivatives is one of the attractive proce-
dures for the preparation of optically active compounds.1–6 We
have also reported on the practical preparation of various optically
active 1,2-diol monotosylates via enzymatic enantioselective
hydrolysis with lipase PS (from Burkholderia cepacia; Amano
Enzyme Inc.), and a methodical study of the substrate specificity
(Scheme 1).7 The length of the R substituent group did not affect
the enantioselectivity, and the enzyme preferred the (R)-enantio-
mer in all substrates.
tleneck with regard to the effective synthesis of the desirable enan-
tiomer. We thus focused on the stereospecific inversion of one
enantiomer of the 1,2-diol monotosylates after enzymatic reaction
and succeeded in the deracemization of the corresponding racemic
compounds by the sequential combination of enzymatic hydrolysis
and Mitsunobu esterification under the optimized reaction condi-
tions.8,9 Based on this process, we obtained the desired single enan-
tiomer of the 1,2-diol monotosylates. In our previous study, we
attempted the stereoinversion only for the compounds bearing a
small substituent (R = Me, CH2Cl, Bu, CH2OBn) and did not examine
the reaction for a compound bearing a longer chain, which possibly
decreases the reactivity. Since the nulceophilicity of sterically hin-
dered alcohols could be low, the Mitsunobu reaction of such
OAc
PPh2
polystyrene
TsO
R
OAc
OAc
lipase PS
(S)-form
OH
DEAD, AcOH
TsO
TsO
buffer–i-Pr2O
toluene
1h, rt
R
R
30 °C
(S)-form
racemate
TsO
R
(R)-form
Scheme 1.
⇑
Corresponding author. Tel.: +81 42 591 7360; fax: +81 42 591 7419.
E-mail address: mkazu@chem.meisei-u.ac.jp (K. Matsumoto).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.023

K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
109
alcohols occurred with an undesired retention of configuration in
some cases.9,10 Thus we decided to take full advantage of our
deracemization procedure for the preparation of optically active
1,2-diol monotosylates bearing a long chain, the compounds of
which are important precursors to natural heterocyclic compounds.
Herein, we have established the deracemization of racemic 1,2-diol
monotosylates bearing a long aliphatic chain, and a new entry for
the efficient syntheses of optically active (S)- and (R)-c-dodecalac-
tone 1 and (S)-coniine 2 as examples demonstrating the validity of
our approach.
On the other hand, substituted piperidines are among the
most ubiquitous nitrogen-containing heterocyclic compounds,
and have attracted a great deal of interest, because they have un-
ique biological activities.17 Thus, many asymmetric synthetic
studies for these kinds of compounds have already been devel-
oped.18 We also planned the synthesis of (S)-coniine 2, which
is an alkaloid that can be isolated from poison hemlock (Conium
maculatum) and is a representative target as a simple substituted
piperidine.19,20 Our synthetic approach to (S)-2 is shown in
Scheme 3. When the deracemization of racemate ( )-5b bearing
a benzyloxy group at the terminus of the substituent occurs,
epoxide (S)-4b could be efficiently prepared in the same manner
as that shown in Scheme 2. After alkylation of (S)-4b, substitu-
tion from the hydroxyl group to the amino group with a stereo-
specific inversion could produce the direct precursor (S)-6 for
(S)-2.20f
2. Results and discussion
2.1. Retrosynthetic studies of compounds 1 and 2
Lactones are well known as important components of aromas
in various foods;11 they also have many biological activities, such
as pheromone, antiviral, antifungal, and antitumor activities.12
Although a number of studies for the preparation of optically ac-
tive lactones have been reported, facile and efficient procedures
for obtaining the desired enantiomerically pure enantiomer of
2.2. Deracemization of 1,2-diol monotosylates bearing a long
aliphatic chain
We first attempted to examine the deracemization of 1,2-diol
monotosylates ( )-5a and 5b bearing a long aliphatic chain. Com-
pounds ( )-5a and 5b were readily prepared according to Scheme 4.
After oxidation of dec-1-ene 8a and 6-benzyloxyhex-1-ene 8b,
which was derived from hex-5-ene-1-ol 7, using a catalytic amount
of OsO4, the highly selective tosylation of the resulting diols ( )-9a
and 9b was carried out using TsCl, Bu2SnO, and Et3N to afford the
corresponding compounds ( )-10a and 10b as the only products,
respectively.9,21 Successive treatment of alcohols ( )-10a and 10b
with acetic anhydride and pyridine gave substrates ( )-5a and
5b, respectively.
For the first step of the deracemization, we examined the lipase
PS-catalyzed hydrolysis of ( )-5a (substrate concentration, 4 mM)
in 0.1 M phosphate buffer (pH 6.5) containing 10% i-Pr2O for 24 h
at 30 °C; the reaction proceeded with excellent enantioselectivity
to afford the unreacted (S)-5a (78% ee) and the resulting (R)-10a
various lactones are still needed.
c-Dodecalactone 1 is a repre-
sentative 5-membered lactone, and was originally isolated from
rove beetles as a defensive secretion.13,14 Compound 1 has also
been isolated from various fruits and butterfats as a natural
flavor;15 it has been reported that the sensory characteristics of
1 are different between the enantiomers.16 We selected both
enantiomers of lactone 1 as the first synthetic target; the retro-
synthetic route of (S)-1 is shown in Scheme 2. In this route,
the optically active epoxide (S)-4a is the key intermediate for
the target compound. If deracemization of the racemate ( )-5a
bearing an octyl group as the long side chain occurs, epoxide
(S)-4a would be efficiently prepared. Furthermore, the stereoin-
version of (S)-5a gives the (R)-enantiomer, which could then be
transformed into (R)-1.
O
OH
O
O
(S)-1
(S)-3
(S)-4a
OAc
OAc
deracemization
TsO
TsO
(S)-5a
( )-5a
Scheme 2.
NHBoc
O
N
H
OBn
OH
· HCl
(S)-2
(S)-6
(S)-4b
OAc
OAc
deracemization
TsO
TsO
OBn
OBn
(S)-5b
( )-5b
Scheme 3.

110
K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
BnBr, NaH
THF, rt
a sequential Mitsunobu reaction (Table 1, entry 1). For the first
OH
OBn
enzymatic hydrolysis, the substrate concentration was increased
to 32 mM (8 times higher than the former value) in order to
achieve an efficient preparative-scale experiment. The reaction
was also carried out for a longer reaction time (48 h), because
the conversion needed to be over 0.5 in order to maintain a high
ee of the final acetate. Even under these conditions, the hydrolysis
proceeded without any inhibition to afford the optically active
compounds (conv. = 0.50, E value = 280). The ees of both products
in the mixed residue were determined directly by HPLC analysis
with a CHIRALCEL AD-H (Daicel Corporation) column. As expected,
for the sequential Mitsunobu reaction using the polymer-sup-
ported PPh3 without a separation step of the products, only the
alcohol (R)-10a (eep, 97% ee) was stereospecifically converted into
the corresponding acetate, and after filtration of the resin, (S)-5a
(eef, 97% ee) was obtained successfully in 81% yield from ( )-5a.
In the same manner, we also attempted the deracemization of
( )-5b bearing a benzyloxy group at the terminus of the substitu-
ent (Table 1, entry 2). Although the enzymatic hydrolysis required
a longer reaction time (72 h) until the conversion was over 0.5, the
reaction also proceeded with excellent enantioselectivity to afford
optically active (S)-5b and (R)-10b as the mixed products
(conv. = 0.51, E value >260). As expected, the sequential Mitsunobu
reaction using polymer supported-PPh3 gave enantiomerically
pure (S)-5b. Finally, we had accomplished the deracemization of
1,2-diol monotosylates bearing a long aliphatic chain.
7
8b (97%)
OH
cat.OsO4, NMO
acetone-H2O, rt
HO
R
R
8a, b
( )-9 (a, 85%; b, 95%)
OH
TsCl, cat.Bu2SnO
Et3N
TsO
R
CH2Cl2, rt
( )-10 (a, 91%; b, 87%)
OAc
Ac2O
TsO
R
pyridine, rt
( )-5 (a, 95%; b, 98%)
a: R = C8H17
b: R = C4H8OBn
Scheme 4.
(99% ee) in 52% and 45% yields, respectively (conv. = 0.44, E
value = 470).22 For the second step, we attempted a modified Mits-
unobu reaction of (R)-10a under the optimized reaction conditions
established in our previous study.9 The heterogeneous reaction
using polymer-supported triphenylphosphine (polystyryldiphe-
nylphosphine, cross-linked with 2% divinylbenzene; 6 equiv) was
carried out with diethyl azodicarboxylate (DEAD, 3 equiv) and
acetic acid (3 equiv) in toluene at room temperature. The reaction
was complete within 1 h along with an inversion of configuration;
furthermore there were no remarkable by-products due to the use
of the polymer-supported PPh3. This result indicates that the
length of the R substituent does not affect the reactivity of our
modified Mitsunobu reaction. Successive reduction of the used
polymer-supported PPh3 with phenylsilane (5 equiv) in toluene
at 110 °C for 48 h gave the refreshed polymer-supported reagent,
which had almost the same activity as the new one.23
It is noteworthy that the ee of the resulting (S)-acetate (eef) can
be easily improved upon by repeating the lipase-mediated hydro-
lysis; our method certainly gives the enantiomerically pure com-
pounds. The reactions of (S)-5a (97% ee) and 5b (98% ee) using
lipase PS in a mixed solvent (i-Pr2O/H2O = 9/1) for 24 and 72 h,
respectively, at 30 °C afforded the enantiomerically pure (S)-5a
and 5b in 89% and 91%, respectively.
2.3. Synthesis of both enantiomers of c-dodecalactone 1
In the next step of our study, we applied this deracemization pro-
cedure to the synthesis of natural products; (S)- -dodecalactone 1
c
was selected as the first target (Scheme 5). Successive treatment of
the acetate (S)-5a with K2CO3 in MeOH gave the key intermediate
(S)-epoxide 4a in 94% yield. The absolute configuration of (S)-4a
{½a 2D6
ꢀ
¼ ꢁ8:2 (c 1.03, CHCl3)) was confirmed by comparing the spe-
cific rotation value with the literature {lit.24
½ ꢀ
a 2D7
¼ þ7:2 (c 0.98,
Next, we examined the deracemization of ( )-5a by a two-step
procedure via the combination of a lipase-mediated hydrolysis and
CHCl3), (R)-form}. The sequential alkylation with allylmagnesium
Table 1
Deracemization of 1,2-diol monotosylates bearing a long aliphatic chaina
OAc
PPh2
polystyrene
TsO
R
OAc
OAc
lipase PS
(S)-5 (ees)
OH
DEAD, AcOH
TsO
TsO
(S)-5 (eef)
buffer–i-Pr2O
R
toluene
1h, rt
R
30 °C
( )-5
TsO
R
(R)-10 (eep)
Entry
R
Enzymatic hydrolysis
eep (%)
Mitsunobu Reaction
Time (h)
ees (%)
Conv. (%)b
E valuec
Total yieldd (%)
eef (%)
1
2
a
b
C8H17
C4H8OBn
48
72
97
100
97
96
0.50
0.51
280
>260
81
82
97
98
a
b
c
The reaction was performed using 32 mM of the substrates as the starting material.
Calculated using ees/(ees + eep).
Calculated using ln[(1 ꢁ conv.)(1ꢁees)]/ln[(1ꢁconv.)(1 + ees)].
d
Calculated from the starting ( )-5 (2 steps).

K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
111
K2CHO3
MeOH, rt
O
bromide in the presence of the catalytic amount of copper(I) bro-
mide afforded the primary alcohol (S)-3 in 81% yield. Finally, a
one-pot oxidation and lactonization with OsO4 and Oxone
(2KHSO5ꢂKHSO4ꢂK2SO4) in DMF, carried out according to a previous
(S)-5a
(S)-4a (94%)
study,14g gave the desired (S)-1 in 55% yield; ½a 2D1
¼ ꢁ43:1 (c 1.01,
ꢀ
OH
CH2=CHCH2MgBr
cat.CuBr
MeOH) {lit.14b
½
a 2D0
ꢀ
¼ ꢁ41:1 (c 5, MeOH)). Conversely, our procedure
can give the opposite enantiomer (Scheme 6). Acetate (S)-5a was
easily transformed into the corresponding alcohol (S)-10a by the
addition of DIBAL at ꢁ78 °C, without any racemization. Next, the
sequential steps consisting of a modified Mitsunobu reaction and
repeating the enzymatic hydrolysis afforded enantiomerically pure
(R)-10a. Although a small amount of acetate (R)-5a (96% ee, 20%)
was recovered, this compound was also reused as the precursor of
(R)-10a. Finally, (R)-10a was converted into epoxide (R)-4a, which
THF,–10 °C
(S)-3 (81%)
O
O
cat.OsO4, NMO
DMF, rt
(S)-1 (55%)
was successfully transformed into (R)-1, ½a D28
¼ þ39:0 (c 0.65,
ꢀ
Scheme 5.
MeOH), by the same procedures as those for the preparation of
(S)-1.
OH
2.4. Synthesis of (S)-coniine 2
DIBAL
TsO
(S)-5a
Finally, we examined the synthesis of (S)-coniine 2 as the next
target (Scheme 7). Epoxide (S)-4b was obtained from (S)-5b, which
was prepared by the deracemization procedure as mentioned
above, by treatment with K2CO3 in MeOH in 99% yield. The abso-
lute configuration of (S)-4b was confirmed by comparing the
THF,–78 °C
(S)-10a (95%)
PPh2
OAc
DEAD, AcOH
toluene, rt
obtained specific rotation value {½a D26
ꢀ
¼ ꢁ5:3 (c 1.14, CHCl3)} to
TsO
the reported one {lit.25
½
a 2D0
ꢀ
¼ ꢁ5:1 (c 2.3, CHCl3)}. The reaction
(R)-5a (89%, 99% ee)
of (S)-4b with vinylmagnesium bromide afforded alcohol (S)-11
in 68% yield. The sequential steps consisting of mesylation and
the azidation with inversion of the stereochemistry gave azide
(R)-12 in 78% yield from (S)-11. The corresponding N-Boc com-
pound (R)-13 was easily obtained by the reduction of (R)-12 with
LiAlH4 and protection of the resulting amino group (91% from
(R)-12). Compound (R)-13 could be a useful key intermediate for
the synthesis of various alkaloids, because the 4-benzyloxybutyl
group could be a direct unit of the 6-membered ring and the allyl
group could become transformed into various substituents.20f The
ee of (R)-13 was determined by HPLC, and confirmed that the reac-
tions from (S)-5b to (R)-13 proceeded without any racemization.
Finally, the synthesis of (S)-coniine 2 as the hydrochloride salt
was efficiently accomplished by an almost same procedure as that
reported in the literature,20f that is, deprotection of the benzyl
OH
lipase PS
TsO
O
buffer–i-Pr2O
30 °C, 15 h
(R)-10a (76%, 100% ee)
+ (R)-5a (22%, 96% ee)
O
(R)-1 (42%, 3 steps)
Scheme 6.
OH
CH2=CHMgBr
cat.CuBr
K2CO3
MeOH, rt
O
(S)-5b
OBn
OBn
THF,–10 °C
(S)-11 (68%)
(S)-4b (99%)
N3
1) LiAlH4 / THF, rt
2) Boc2O / THF, rt
1) MsCl, Et3N / CH2Cl2, rt
2) NaN3 / DMF, 40 °C
OBn
(R)-12 (78%, 2 steps)
NHBoc
NHBoc
Pd-C, H2
EtOH, rt
OBn
OH
(R)-13 (91%, 2 steps)
(S)-6
1) MsCl, Et3N / CH2Cl2, rt
2) NaH / DMF, rt
4 M HCl aq
N
N
dioxane-MeOH, rt
Boc
(S)-14 (91%, 3 steps)
H
· HCl
(S)-2 (98%)
Scheme 7.

112
K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
group with reduction of the C@C bond of (R)-13, mesylation of the
hydroxyl group of (S)-6 and cyclization with NaH to give
(S)-14 in 91% yield (3 steps), and deprotection of the Boc group
Under an argon atmosphere, to Bu2SnO (30.0 mg, 0.121 mmol)
were added solutions of ( )-9a (1.31 g, 5.92 mmol) in CH2Cl2
(15 mL), TsCl (1.45 g, 7.11 mmol) in CH2Cl2 (10 mL), and Et3N
(1.00 mL, 7.17 mmol). The mixture was stirred for 1 h at room tem-
perature, after which the reaction was stopped with 2 M HCl at 0 °C.
The products were extracted with CH2Cl2 (ꢃ3), and the organic
layer was washed with H2O, sat. NaHCO3 aq, and brine, and dried
over Na2SO4. After evaporation under reduced pressure, the residue
was purified by flash column chromatography on silica gel (hexane/
AcOEt = 9/1) to give ( )-2-hydroxydecyl tosylate 10a as a colorless
oil (1.18 g, 91%); IR (neat) 3547, 2926, 2853, 2363, 1595, 1470,
to afford (S)-2ꢂHCl in 98% yield; ½a D20
¼ þ5:7 (c 1.12, EtOH)
ꢀ
(lit.19
½
a 2D0
ꢀ
¼ þ5:2 (c 1.0, EtOH)).
3. Conclusion
Herein we have established a facile deracemization procedure
for racemic 1,2-diol monotosylates bearing a long aliphatic chain,
which are useful intermediate in the synthesis of heterocyclic com-
pounds. Enantiomerically pure (S)-5a and 5b were efficiently pre-
pared as single products. Compound (S)-5a was successfully
1348, 1175, 1096, 957, 893, 843, 818, 675 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d = 0.88 (t, J = 6.5 Hz, 3H), 1.20–1.33 (m, 12H),
1.35–1.46 (m, 2H), 2.06 (d, J = 4.5 Hz, 1H), 2.46 (s, 3H), 3.80–3.87
(m, 1H), 3.88 (dd, J1 = 7.0 Hz, J2 = 9.5 Hz, 1H), 4.04 (dd, J1 = 2.5 Hz,
J2 = 9.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d = 14.1, 21.6, 22.6, 25.2, 29.2, 29.37,
29.39, 31.8, 32.6, 69.5, 74.0, 127.9, 129.9, 132.6, 145.0; MS (EI) m/
z (relative intensities) 328 (M+, 1.4), 298 (56), 172 (18), 156 (59)
143 (100), 138 (65), 91 (100); HRMS (EI) m/z 328.1712 (328.1708
Calcd for C17H28O4S, M+).
transformed into both enantiomers of
c-dodecalactone 1, while
compound (S)-5b was converted into (S)-coniine 2 containing a
piperidine ring. Further investigations for the application of the
deracemization procedure are currently in progress.
4. Experimental
4.1. General
Under an argon atmosphere, acetic anhydride (2.60 mL,
23.2 mmol) was added to a solution of ( )-10a (1.51 g, 4.60 mmol)
in pyridine (10 mL), and the mixture was stirred for 4 h at room
temperature. After the mixture was diluted with AcOEt, the organic
layer was washed with 2 M HCl, brine, sat. NaHCO3 aqueous solu-
tion, and brine, and dried over Na2SO4. After evaporation, the res-
idue was purified by column chromatography on silica gel
(hexane/AcOEt = 9/1) to give ( )-5a as a colorless oil (1.62 g,
95%); IR (neat) 2926, 2854, 1744, 1597, 1458, 1368, 1236, 1177,
1H (500 or 300 MHz) and 13C (125 or 75 MHz) NMR spectra
were measured on a JEOL JNM a-500 or AL-300 with tetramethyl-
silane (TMS) as the internal standard. IR spectra were recorded
with Shimadzu IR Prestige-21 spectrometers. Mass spectra were
obtained with a JEOL EI/FAB mate BU25 Instrument by the EI meth-
od and a JEOL JMS-T100 by the ESI-TOF method in MeOH–H2O
solution including AcONa. Optical rotations were measured with
a Jasco DIP-1000 polarimeter. HPLC data were obtained on Shima-
1098, 980, 816, 667 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 0.88
;
dzu LC-10ADVP, SPD-10AVP, and
l7 Data Station (System Instru-
(t, J = 6.5 Hz, 3H), 1.12–1.33 (m, 12H), 1.46–1.64 (m, 2H), 1.98
(s, 3H), 2.46 (s, 3H), 4.04 (dd, J1 = 5.0 Hz, J2 = 11.0 Hz, 1H), 4.10
(dd, J1 = 3.5 Hz, J2 = 11.0 Hz, 1H), 4.87–5.01 (m, 1H), 7.36
(d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d = 14.1, 20.9, 21.6, 22.6, 24.9, 29.1, 29.2, 29.3, 30.1, 31.8,
70.0, 70.9, 127.9, 129.8, 132.7, 144.9, 170.4; MS (EI) m/z (relative
intensities) 370 (M+, 4.1), 228 (21), 199 (14), 172 (24), 155 (73),
138 (64), 96 (36), 91 (100), 81 (32), 69 (42); HRMS (EI) m/z
370.1814 (370.1814 Calcd for C19H30O5S, M+).
ments Co., Ltd) or Shimadzu LC-20AD, SPD-20A, and SmartChrom
(KYA technologies cooperation). GLC data were obtained on GL Sci-
ences GC 353B and l7 Data Station (System Instruments Co., Ltd)
using CP-Cyclodextrin-B-236-M19 (Agilent Technologies, Inc.;
0.25 mm ꢃ 50 m; carrier gas, He; head pressure, 2.4 kg/cm2). E.
Merck Kieselgel 60 F254 Art.5715 was used for analytical TLC. Pre-
parative TLC was performed on E. Merck Kieselgel 60 F254 Art.5744.
Column chromatography was performed with Silica Gel 60 N (63–
210 lm, Kanto Chemical Co., Inc.). All other chemicals were ob-
tained from commercial sources. A polymer-bound phosphine re-
agent was purchased from Aldrich [polystyryldiphenylphosphine,
cross-linked with 2% divinylbenzene (No. 366445).].
4.2.2. ( )-2-Acetoxy-6-benzyloxyhexyl tosylate 5b
Under an argon atmosphere, to a suspension of NaH (55% in oil,
2.62 g, 60 mmol) in THF (10 mL) were added a solution of hex-5-
en-1-ol (7, 4.01 g, 40.0 mmol) in THF (30 mL) and benzyl bromide
(5.09 mL, 42.9 mmol) at 0 °C. The mixture was stirred for 14 h at
room temperature, after which the reaction was quenched with a
0.1 M phosphate buffer (pH 6.5) at 0 °C. The products were ex-
tracted with AcOEt (ꢃ4), and the organic layer was washed with
brine and dried over Na2SO4. After evaporation under reduced
pressure, the residue was purified by flash column chromatogra-
phy on silica gel (hexane?hexane/AcOEt = 5/1) to give 6-benzyl-
4.2. Preparation of the substrates for enzymatic reactions
4.2.1. ( )-2-Acetoxydecyl tosylate 5a
To a solution of dec-1-ene 8a (1.00 g, 7.13 mmol) in acetone
(80 mL) and H2O (10 mL) were added 4-methylmorpholine
N-oxide (NMO, 1.72 g, 14.3 mmol), and a catalytic amount of
OsO4. The mixture was then stirred for 2.5 h at room temperature.
After the addition of Na2S2O4, the mixture was filtered through a
Celite pad. The filtrate was diluted with AcOEt, and washed with
brine (ꢃ2), and dried over Na2SO4. After evaporation, the residue
was purified by flash column chromatography on silica gel (AcOEt)
to give ( )-decan-1,2-diol 9a as a colorless solid (1.05 g, 85%); mp
41.5–42.3 °C; IR (KBr) 3308, 3207, 2922, 2849, 1468, 1142, 1099,
oxyhex-1-ene
7 as a
colorless oil (7.42 g, 98%); 1H NMR
(300 MHz, CDCl3) d = 1.41–1.52 (m, 2H), 1.55–1.66 (m, 2H), 2.02–
2.10 (m, 2H), 3.47 (t, J = 7.0 Hz, 2H), 4.50 (s, 2H), 4.88–4.97
(m, 1H), 4.97–5.03 (m, 1H), 5.80 (tdd, J1 = 6.5 Hz, J2 = 10.5 Hz,
J3 = 17.0 Hz, 1H), 7.22–7.39 (m, 5H); 13C NMR (75 MHz, CDCl3)
d = 25.5, 29.2, 33.5, 70.2, 72.8, 114.5, 127.5, 127.6, 128.3, 138.6,
138.7; HRMS (ESI) m/z 213.1253 (213.1255 Calcd for C13H18ONa,
[M+Na]+).
1072, 978, 874, 721 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 0.88
;
(t, J = 6.5 Hz, 3H), 1.20–1.37 (m, 11H), 1.38–1.48 (m, 3H), 2.63
(s, 2H), 3.42 (dd, J1 = 7.5 Hz, J2 = 11.0 Hz, 1H), 3.64 (dd, J1 = 2.5 Hz,
J2 = 11.0 Hz, 1H), 3.70 (tdd, J1 = 2.5 Hz, J2 = 5.0 Hz, J3 = 7.5 Hz, 1H);
13C NMR (125 MHz, CDCl3) d = 14.1, 22.6, 25.5, 29.2, 29.5, 29.6,
31.8, 33.1, 66.8, 72.3; MS (EI) m/z (relative intensities) 156
([MꢁH2O]+, 0.8), 143 (93), 112 (16), 83 (100) 69 (100); HRMS
(EI) m/z 174.1619 (174.1620 Calcd for C10H22O2, M+).
According to the procedure for the preparation of ( )-9a, 7 was
converted into ( )-6-benzyloxyhexan-1,2-diol 9b as a colorless so-
lid (95%); IR (neat) 3385, 2938, 2862, 1454, 1364, 1206, 1098,
1072, 737, 698 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 1.35–1.48
;
(m, 3H), 1.48–1.57 (m, 1H), 1.57–1.70 (m, 2H), 2.80 (br s, 1H),
2.94 (br s, 1H), 3.34–3.42 (m, 1H), 3.43–3.53 (m, 1H), 3.48 (dt,

K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
113
J1 = 1.0 Hz, J2 = 6.5 Hz, 1H), 3.54–3.62 (m, 1H), 3.62–3.72 (m, 1H),
4.49 (s, 2H), 7.25–7.38 (m, 5H); 13C NMR (75 MHz, CDCl3)
d = 22.2, 29.5, 32.8, 66.7, 70.2, 72.1, 72.9, 127.6, 127.7, 128.3,
138.4; HRMS (ESI) m/z 247.1272 (247.1310 Calcd for C13H20O3Na,
[M+Na]+).
by flash column chromatography on silica gel (hexane/AcOEt = 9/1)
to give (S)-5a (100% ee) as a colorless oil (3.60 g, 89%); ½a D22
¼
ꢀ
ꢁ13:7 (c 0.58, CHCl3).
The deracemization of ( )-5b was carried out by the same pro-
cedure to afford enantiomerically pure (S)-5b as a colorless oil [75%
According to the procedure for the preparation of ( )-10a, com-
pound ( )-9b was converted into ( )-6-benzyloxy-2-hydroxyhexyl
tosylate 10b as a colorless oil (87%); IR (neat) 3428, 3030, 2941,
from ( )-5b]; ½a 2D6
¼ ꢁ9:7 (c 2.7, CHCl3). The ees of (S)-5b and (R)-
ꢀ
10b were determined by HPLC analysis. HPLC conditions: column,
CHIRALCEL AD-H; eluent, hexane/2-propanol = 80/20; flow rate,
0.5 mL/min; 254 nm; temperature, 25 °C; retention time, 5b: 22
(S) and 23 (R) min, 10b: 25 (R) and 35 (S) min.
2864, 1597, 1454, 1360, 1176 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d = 1.33–1.45 (m, 3H), 1.45–1.54 (m, 1H), 1.54–1.66 (m, 2H), 2.35
(d, J = 4.5 Hz, 1H), 2.44 (s, 3H), 3.78–3.85 (m, 1H), 3.87 (dd,
J1 = 7.0 Hz, J2 = 10.0 Hz, 1H), 4.00 (dd, J1 = 3.0 Hz, J2 = 10.0 Hz, 1H),
4.48 (s, 2H), 7.25–7.37 (m, 7H), 7.79 (d, J = 8.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d = 21.6, 21.9, 29.4, 32.3, 69.3, 69.9, 72.9, 73.9,
127.5, 127.6, 127.9, 128.3, 129.9, 132.6, 138.4, 145.0; HRMS (ESI)
m/z 401.1392 (401.1399 Calcd for C20H26O5SNa, [M+Na]+).
All spectroscopic data (1H and 13C NMR, IR, and MS) were in full
agreement with those of the racemate.
4.4. Synthesis of (S)-c-dodecalactone 1
To a solution of (S)-5a (1.32 g, 3.56 mmol) in MeOH (10 mL) was
added K2CO3 (4.91 g, 35.6 mmol) at 0 °C. After the mixture was
stirred for 1 h at room temperature, the reaction was stopped with
a 0.1 M phosphate buffer (pH 6.5), and the products were extracted
with Et2O (ꢃ3). The organic layer was washed with brine and dried
over Na2SO4. After evaporation, the residue was purified by flash
column chromatography on silica gel (CH2Cl2) to give (S)-2-octy-
According to the procedure for the preparation of ( )-5a,
( )-10b was converted into ( )-6-benzyloxy-2-hydroxyhexyl tosyl-
ate 5b as a colorless oil (98%); IR (neat) 3208, 2940, 2862, 1742,
1597, 1456, 1364, 1238, 1177 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d = 1.23–1.42 (m, 2H), 1.50–1.65 (m, 4H), 1.97 (s, 3H), 2.44 (s,
3H), 3.43 (t, J = 6.5 Hz, 2H), 4.03 (dd, J1 = 5.0 Hz, J2 = 11.0 Hz, 1H),
4.09 (dd, J1 = 3.5 Hz, J2 = 11.0 Hz, 1H), 4.48 (s, 2H), 4.95 (ddt,
J1 = 3.5 Hz, J2 = 5.5 Hz, J3 = 8.0 Hz, 1H), 7.26–7.37 (m, 7H), 7.78 (d,
J = 8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) d = 20.8, 21.6, 21.7,
29.3, 29.9, 69.7, 69.9, 70.8, 72.9, 127.5, 127.6, 127.9, 128.3, 129.8,
132.8, 138.4, 144.9, 170.3; HRMS (ESI) m/z 443,1506 (443,1504
Calcd for C22H28O6SNa, [M+Na]+).
loxirane 4a as a colorless oil (518 mg, 94%); ½a D26
¼ ꢁ8:2 (c 1.03,
ꢀ
CHCl3); IR (neat) 2926, 2855, 1466, 1410, 1377, 1260, 1215,
1190, 1129, 916, 833 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 0.88
;
(t, J = 7.0 Hz, 3H), 1.21–1.39 (m, 10H), 1.39–1.56 (m, 4H), 4.04
(dd, J1 = 2.5 Hz, J2 = 5.0 Hz, 1H), 2.75 (dd, J1 = 4.0 Hz, J2 = 5.0 Hz,
1H), 2.91 (ddt, J1 = 2.5 Hz, J2 = 4.0 Hz, J3 = 5.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d = 14.0, 22.6, 26.0, 29.1, 29.4, 29.5, 31.8, 32.4,
47.1, 52.4; MS (EI) m/z (relative intensities) 156 (M+, 1.0), 138
(11), 113 (14), 83 (36), 71 (100), 68 (36), 58 (79); HRMS (EI) m/z
156.1477 (156.1514 Calcd for C10H20O, M+).
4.3. Typical procedure for the deracemization of acetates 5 with
lipase PS and the sequential Mitsunobu inversion using
polymer-bound triphenylphosphine
Under an argon atmosphere, to a mixture of copper (I) bromide
(65.0 mg, 0.509 mmol) and allylmagnesium bromide (4.60 mL,
1.0 M THF solution) was added a solution of (S)-4a (477 mg,
3.05 mmol) in THF (19 mL) at ꢁ10 °C and stirred for 1 h. The reac-
tion was quenched with sat. NH4Cl aq, and the products were ex-
tracted with Et2O (ꢃ3). The organic layer was washed with brine
and dried over Na2SO4. After evaporation, the residue was purified
by flash column chromatography on silica gel (hexane/AcOEt = 20/
1) to give (S)-1-tridecen-5-ol 3 as a colorless oil (491 mg, 81%);
To a 1-L Erlenmeyer flask containing 2.50 g (6.75 mmol; sub.
conc., 34 mM) of ( )-5a were added 20 mL of i-Pr2O and 180 mL
of 0.1 M phosphate buffer (pH 6.5). To the mixture was added
375 mg of lipase PS (>23 u/mg, using olive oil), and the solution
was incubated for 48 h at 30 °C. The products were extracted with
AcOEt (ꢃ3), washed with brine and dried over Na2SO4. After the
same reaction was carried out, and the combined organic layer
was evaporated in vacuo, the residue was filtered through a small
amount of silica gel (10 g; eluent, AcOEt), and the filtrate was con-
centrated in vacuo. The mixture of (S)-5a (97%) and (R)-10a (97%)
(4.68 g) was used for the sequential reaction without further puri-
fication. The ees of (S)-5a and (R)-10a were determined by HPLC
analysis. HPLC conditions: column, CHIRALCEL AD-H (Daicel Cor-
poration; eluent, hexane/2-propanol = 95/5; flow rate, 0.5 mL/
min; 254 nm; temperature, 25 °C; retention time, 5a: 20 (S) and
23 (R) min, 10a: 48 (R) and 71 (S) min.
Under an argon atmosphere, to a polymer-supported PPh3
(13.1 g, ca. 40.3 mmol, ca. 3.08 mmol PPh3/g resin) was added a
solution of (S)-5a and (R)-10a (4.68 g) in toluene (60 mL), AcOH
(1.15 ml, 20.2 mmol), and DEAD (9.20 mL, 20.2 mmol, 40% toluene
solution), and the suspension was stirred for 1 h at rt. After the
mixture was filtered, the filtrate was diluted with AcOEt, washed
with sat. aq. NaHCO3 and brine, and dried over Na2SO4. After evap-
oration, the residue was purified by flash column chromatography
on silica gel (hexane/AcOEt = 9/1) to give (S)-5a (97% ee) as a col-
orless oil [4.04 g, 81% from ( )-5a].
½
a 2D4
ꢀ
¼ ꢁ3:0 (c 1.05, MeOH); IR (neat) 3310, 2926, 2854, 2359,
1641, 1458, 1215, 1192, 993, 910 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d = 0.88 (t, J = 7.0 Hz, 3H), 1.21–1.34 (m, 12H), 1.38–1.48 (m, 3H),
1.48–1.61 (m, 2H), 2.08–2.16 (m, 1H), 2.16–2.26 (m, 1H), 3.57–
3.65 (m, 1H), 4.97 (tdd, J1 = 1.0 Hz, J2 = 2.0 Hz, J3 = 10.0 Hz, 1H),
5.05 (ddd, J1 = 1.5 Hz, J2 = 3.5 Hz, J3 = 17.0 Hz, 1H), 5.85 (ddt,
J1 = 6.5 Hz, J2 = 10.0 Hz, J3 = 17.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 14.1, 22.6, 25.6, 29.2, 29.6, 19.7, 30.1, 31.9, 36.4, 37.5, 71.5,
114.7, 138.6; MS (EI) m/z (relative intensities) 198 (M+, 1.0), 180
(16), 123 (16), 96 (58), 83 (77), 81 (100), 71 (39), 67 (97); HRMS
(EI) m/z 198.2002 (198.1984 Calcd for C13H26O, M+).
Under an argon atmosphere, to a solution of (S)-3 (99.7 mg,
0.503 mmol) in DMF (9 mL) were added a catalytic amount of
OsO4 and NMO (1.24 g, 2.02 mmol) at 0 °C, and the mixture was
stirred overnight at room temperature. After the addition of
Na2SO3, the mixture was filtered through a Celite pad. The filtrate
was diluted with CH2Cl2, and washed with 2 M HCl (ꢃ6), brine, and
dried over Na2SO4. After evaporation, the residue was purified by
flash column chromatography on silica gel (CH2Cl2) to give (S)-1
as a colorless oil. This was further purified by Kugelrohr distillation
To a 1-L Erlenmeyer flask containing 4.04 g (10.9 mmol; sub.
conc., 34 mM) of (S)-5a (97% ee) were added 32 mL of i-Pr2O and
288 mL of 0.1 M phosphate buffer (pH 6.5). To the mixture was
added 600 mg of lipase PS, and the solution was incubated for
24 h at 30 °C. After the mixture was filtered through a Celite pad,
the products were extracted with AcOEt (ꢃ3), washed with brine,
and dried over Na2SO4. After evaporation, the residue was purified
(bath temperature, 200 °C, 20 mmHg) (55.0 mg, 55%);
½
a 2D1
ꢀ
¼
ꢁ43:1 (c 1.01, MeOH); IR (neat) 3528, 2926, 2855, 1775, 1653,
1458, 1352, 1180, 1015, 980, 914 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d = 0.88 (t, J = 7.0 Hz, 3H), 1.21–1.50 (m, 12H), 1.55–1.66 (m, 1H),

114
K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
1.69–1.79 (m, 1H), 1.85 (dtd, J1 = 8.0 Hz, J2 = 9.5 Hz, J3 = 12.5 Hz,
1H), 2.32 (tdd, J1 = J2 = 6.5 Hz, J3 = 12.5 Hz, 1H), 2.53 (dd,
J1 = 0.5 Hz, J2 = 9.5 Hz, 1H), 2.54 (d, J = 10.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d = 14.0, 22.6, 25.2, 28.0, 28.8, 29.1, 29.3, 29.4,
31.8, 35.5, 81.0, 177.3; MS (EI) m/z (relative intensities) 198 (M+,
5.6), 180 (26), 138 (24), 128 (96), 114 (26), 96 (40), 85 (100), 69
(53); HRMS (EI) m/z 198.1650 (198.1620 Calcd for C12H22O2, M+).
to give (S)-8-benzyloxyoct-1-en-4-ol 11 as a colorless oil (189 mg,
69%); ½a 2D6
ꢀ
¼ ꢁ3:9 (c 0.69, CHCl3); IR (neat) 3412, 2934, 2860, 1638,
1456, 1364, 1101, 912, 734, 698 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d = 1.40–1.58 (m, 3H), 1.58–1.74 (m, 3H), 2.10 (s, 1H), 2.10–2.17
(m, 1H), 2.26–2.36 (m, 1H), 3.48 (t, J = 6.5 Hz, 2H), 3.62–3.67 (m,
1H), 4.50 (s, 2H), 5.09–5.13 (m, 1H), 5.13–5.16 (m, 1H), 5.76–5.87
(m, 1H), 7.25–7.37 (m, 5H); 13C NMR (125 MHz, CDCl3) d = 22.3,
29.6, 36.5, 41.9, 70.2, 70.5, 72.9, 118.1, 127.5, 127.6, 128.3, 134.8,
138.5; HRMS (ESI) m/z 257.1510 (257.1518 Calcd for C15H22O2Na,
[M+Na]+).
4.5. Synthesis of (R)-c-dodecalactone 1
Under an argon atmosphere to a solution of (S)-5a (100% ee,
2.00 g, 5.39 mmol) in THF (30 mL) was added DIBAL (21.6 mL,
1.0 M toluene solution) at ꢁ78 °C. After the mixture was stirred
for 1 h, the reaction was stopped with a 0.1 M phosphate buffer
(pH 6.5). After the addition of 2 M HCl to the mixture, the products
were extracted with CH2Cl2 (ꢃ3), and the organic layer was
washed with brine, and dried over Na2SO4. After evaporation under
reduced pressure, the residue was purified by flash column chro-
matography on silica gel (hexane/AcOEt = 4/1) to give (S)-10a as
Under an argon atmosphere to a solution of (S)-11 (179 mg,
0.763 mmol) in CH2Cl2 (3.5 mL) were added triethylamine
(117 lL, 0.842 mmol) and methanesulfonyl chloride (65 lL,
0.838 mmol) at 0 °C. After the mixture was stirred for 1 h at room
temperature, the reaction was stopped with H2O. The products
were extracted with Et2O (ꢃ3), and the organic layer was washed
with brine, and dried over Na2SO4. After evaporation, the residue
(231 mg) was used in the following reaction without further puri-
fication. Under an argon atmosphere, to a solution of the residue in
DMF (3.5 mL) was added sodium azide (74.8 mg, 1.15 mmol) at
room temperature, and the mixture was stirred for 16 h at 40 °C.
After the mixture was stopped with a 0.1 M phosphate buffer
(pH 6.5), the products were extracted with Et2O (ꢃ3), washed with
brine, and dried over Na2SO4. After evaporation, the residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt = 20/1) to give (R)-4-azido-8-benzyloxyoct-1-ene 12 as a
colorless oil 156 mg, 79% from (S)-11); 1H NMR (500 MHz, CDCl3)
d = 1.41–1.68 (m, 6H), 2.28–2.32 (m, 2H), 3.30–3.36 (m, 1H), 3.48
(t, J = 6.5 Hz, 2H), 4.50 (s, 2H), 5.08–5.22 (m, 2H), 5.80 (ddt,
J1 = 7.0 Hz, J2 = 10.0 Hz, J3 = 17.0 Hz, 1H), 7.26–7.40 (m, 5H); 13C
NMR (75 MHz, CDCl3) d = 22.8, 29.5, 33.7, 38.7, 62.2, 70.0, 72.9,
118.1, 127.5, 127.6, 128.4, 133.9, 138.5; HRMS (ESI) m/z
282.1559 (282.1582 Calcd for C15H21NO2Na, [M+Na]+).
a colorless oil (1.68 g, 95%); ½a D27
¼ þ5:7 (c 1.73, CHCl3).
ꢀ
According to the procedure for the preparation of (S)-5a from
(R)-10a, compound (S)-10a was converted into (R)-5a (99% ee) as
a colorless oil (89%); ½a D26
¼ þ10:1 (c 1.50, CHCl3).
ꢀ
To a 100-mL Erlenmeyer flask containing 74.3 mg (0.201 mmol;
sub. conc., 10 mM) of (R)-5a (99% ee) were added 2 mL of i-Pr2O
and 18 mL of 0.1 M phosphate buffer (pH 6.5). To the mixture
was added 15 mg of lipase PS, and the solution was incubated for
15 h at 30 °C. The products were extracted with AcOEt (ꢃ3),
washed with brine, and dried over Na2SO4. After evaporation, the
residue was purified by flash column chromatography on silica
gel (hexane/AcOEt = 6/1) to give (R)-10a (100% ee) as a colorless
solid (50.2 mg, 76%); ½a D25
¼ þ6:7 (c 0.91, CHCl3). The remaining
ꢀ
(R)-5a (96% ee) was also recovered in 22% yield (16.2 mg).
According to the procedure for the preparation of (S)-4a, com-
pound (R)-10a was converted into (R)-4a as a colorless oil (81%);
Under an argon atmosphere, to a suspension of lithium alumi-
num hydride (32.2 mg, 0.849 mmol) was added a solution of
(S)-12a (144 mg, 0.556 mmol) in THF (6 mL) at 0 °C. After the mix-
ture was stirred for 1 h at room temperature, the reaction was
quenched with H2O (0.5 mL) and potassium sodium tartrate tetra-
hydrate. After the solution had cleared, the mixture was dried over
Na2SO4. After filtration with AcOEt and evaporation, the products
were extracted with CH2Cl2 (ꢃ3), and the organic layer was washed
with brine, and dried over Na2SO4. After evaporation under reduced
pressure, the residue (136 mg) was used in the following reaction
without further purification. Under an argon atmosphere, to a solu-
tion of the residue in THF (3.5 mL) was added a solution of di-tert-
butyl dicarbonate (Boc2O, 150 mg, 0.667 mmol) in THF (3 mL), and
the mixture was stirred for 3 h at room temperature. After the mix-
ture was concentrated in vacuo, the residue was purified by flash
column chromatography on silica gel (hexane/AcOEt = 6/1) to give
(R)-8-benzyloxy-4-(tert-butoxycarbonyl)aminooct-1-ene 13 as a
colorless oil [100% ee, 169 mg, 91% from (R)-12]. The ee of (R)-12
was determined by HPLC analysis. HPLC conditions: column, CHI-
RALCEL AD-H; eluent, hexane/2-propanol = 90/10; flow rate,
0.5 mL/min; 254 nm; temperature, 25 °C; retention time, 10.6 (S)
½
a 2D5
a 2D4
a 2D8
ꢀ
¼ þ7:3 (c 0.97, CHCl3).
According to the procedure for the preparation of (S)-3, com-
pound (R)-4a was converted into (R)-3 as a colorless oil (92%);
¼ þ2:4 (c 0.86, MeOH).
According to the procedure for the preparation of (S)-1, com-
pound (R)-3 was converted into (R)-1 as a colorless oil (55%);
¼ þ39:0 (c 0.65, MeOH).
All of the spectroscopic data (1H and 13C NMR, IR, and MS) of the
½
ꢀ
½
ꢀ
intermediates and the final product were in full agreement with
those of the opposite enantiomers.
4.6. Synthesis of (S)-coniine 2
According to the procedure for the preparation of (S)-4a, com-
pound (S)-5b was converted into (S)-2-(4-benzyloxybutyl)oxirane
4b as a colorless oil (99%); ½a D26
¼ ꢁ5:3 (c 1.14, CHCl3); IR (neat)
ꢀ
3032, 2938, 2859, 1454, 1364, 1260, 1204, 1101, 837, 736,
698 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 1.49–1.60 (m, 3H), 1.61–
;
1.73 (m, 3H), 2.46 (dd, J1 = 2.5 Hz, J2 = 5.0 Hz, 1H), 2.75
(t, J = 4.5 Hz, 1H), 2.85–2.95 (m, 1H), 3.49 (t, J = 6.5 Hz, 2H), 4.50
(s, 2H), 7.25–7.38 (m, 5H); 13C NMR (75 MHz, CDCl3) d = 22.7,
29.5, 32.3, 47.0, 52.2, 70.1, 72.9, 127.5, 127.6, 128.3, 138.5; HRMS
(ESI) m/z 229.1183 (229.1205 Calcd for C13H18O2Na, [M+Na]+).
Under an argon atmosphere, to a mixture of copper (I) bromide
(26.5 mg, 0.185 mmol) and vinylmagnesium bromide (1.75 mL,
1.0 M THF solution) was added a solution of (S)-4b (242 mg,
1.17 mmol) in THF (4.5 mL) at ꢁ10 °C, and stirred for 1 h. The reac-
tion was quenched in sat. NH4Cl aq, and the products were ex-
tracted with Et2O (ꢃ3). The organic layer was washed with brine,
and dried over Na2SO4. After evaporation, the residue was purified
by flash column chromatography on silica gel (hexane/AcOEt = 4/1)
and 12.2 (R) min. ½a D26
¼ þ13:8 (c 1.04, CHCl3); IR (neat) 3408,
ꢀ
2976, 2934, 2859, 1684, 1508, 1458, 1364, 1248, 1171, 1101, 914,
735, 698 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 1.30–1.56 (m, 3H),
;
1.56–1.67 (m, 3H), 1.43 (s, 9H), 2.13–2.26 (m, 2H), 3.46 (t,
J = 6.5 Hz, 2H), 3.62 (br s, 1H), 4.33 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H),
5.04–5.06 (m, 1H), 5.06–5.09 (m, 1H), 5.70–5.81 (m, 1H), 7.26–
7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) d = 22.6, 27.4, 28.4, 29.5,
34.4, 39.5, 50.0, 70.1, 72.8, 78.9, 117.5, 127.4, 127.6, 128.3, 134.5,
138.5, 155.5; HRMS (ESI) m/z 356.2196 (356.2202 Calcd for
C
20H31NO3Na, [M+Na]+).
To a solution of (R)-12 (155 mg, 0.465 mmol) in EtOH (4 mL)
was 10% Pd-C (47.0 mg), and the solution was degassed under re-

K. Matsumoto et al. / Tetrahedron: Asymmetry 24 (2013) 108–115
115
Chem. 1986, 50, 375–380; (b) Hamaguchi, S.; Ohashi, T.; Watanabe, K. Agric.
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Chen, L.; Wong, C.-H. J. Org. Chem. 1990, 55, 4897–4901.
duced pressure. The reaction was carried out under a hydrogen
atmosphere, and stirred for 1 h at room temperature. After the
mixture was filtered with AcOEt and evaporated in vacuo, the res-
idue (S)-6 (122 mg) was used in the following reaction without fur-
ther purification. Under an argon atmosphere, to a solution of (S)-6
2. For the enzymatic esterification of 1,2-diol monotosylates in an organic
solvent, see: (a) Chênevert, R.; Gagnon, R. J. Org. Chem. 1993, 58, 1054–1057; (b)
Boaz, N. W.; Zimmerman, R. L. Tetrahedron: Asymmetry 1994, 5, 153–156; (c)
Boaz, N. W.; Falling, S. N.; Moore, M. K. Synlett 2005, 1615–1617.
3. For the enzymatic esterification of 1,2-diol monotosylates and hydrolysis in an
organic solvent, see: Neagu, C.; Hase, T. Tetrahedron Lett. 1993, 34, 1629–1630.
4. For the enzymatic esterification of 1,2-diol monotosylates and enzymatic
alcoholysis in an organic solvent, see: Chen, C.-S.; Liu, Y.-C. Tetrahedron Lett.
1989, 30, 7165–7168.
5. For the enzymatic hydrolysis of acyl derivatives of 1,2-diol monotosylates in an
aqueous medium and enzymatic alcoholysis in an organic solvent, see: Chen,
C.-S.; Liu, Y.-C.; Marsella, M. J. Chem. Soc., Perkin Trans. 1 1990, 2559–2561.
6. For the enantioselective decomposition of 1,2-diol monotosylate by
microorganisms, see: Saito, Y.; Nakamura, T. JP 10057096, 1998.
7. (a) Shimada, Y.; Sato, H.; Minowa, S.; Matsumoto, K. Synlett 2008, 367–370; (b)
Shimada, Y.; Sato, H.; Mochizuki, S.; Matsumoto, K. Synlett 2008, 2981–2984.
8. Mitsunobu, O. Synthesis 1981, 1–28.
9. Shimada, Y.; Usuda, K.; Okabe, H.; Suzuki, T.; Matsumoto, K. Tetrahedron:
Asymmetry 2009, 20, 2802–2808.
10. Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102–
11113.
11. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 1–42.
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4635–4638.
in CH2Cl2 (2.5 mL) were added triethylamine (71.5
lL, 0.514
mmol) and methanesulfonyl chloride (40.0 L, 0.516 mmol) at
l
0 °C. After the mixture was stirred for 1 h at room temperature,
the reaction was stopped with H2O. The products were extracted
with AcOEt (ꢃ3), and the organic layer was washed with brine,
and dried over Na2SO4. After filtration and evaporation, the residue
(162 mg) was used in the following reaction without further puri-
fication. Under an argon atmosphere, to a suspension of sodium
hydride (55% in oil, 30.7 mg, 0.704 mmol) was added a solution
of the residue in DMF (2.5 mL) at 0 °C. After the mixture was stirred
for 1 h at room temperature, the reaction was quenched with H2O,
and the products were extracted with AcOEt (ꢃ3), washed with
brine, and dried over Na2SO4. After evaporation, the residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt = 9/1) to give (S)-N-tert-butoxycarbonyl-2-propylpiperidine
14 as a colorless oil (95.1 mg, 90% from (R)-13); ½a D25
¼ þ30:9
ꢀ
(c 0.98, CHCl3); IR (neat) 2932, 2864, 1694, 1416, 1364, 1269,
14. For representative examples of the synthesis of optically active
c-
1173, 1148, 1047, 878, 768 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
dodecalactone 1, see: (a) Sugai, T.; Mori, K. Agric. Biol. Chem. 1984, 48, 2497–
2500; (b) Roder, H.; Helmchen, G.; Peters, E.-M.; Peters, K.; von Schnering, H.-G.
Angew. Chem., Int. Ed. Engl. 1984, 23, 898–899; (c) Chattopadhyay, S.;
Mamdapur, V. R.; Chadha, M. S. Tetrahedron 1990, 46, 3667–3672; (d) Gocho,
S.; Tabogami, N.; Inagaki, M.; Kawabata, C.; Komai, T. Biosci. Biotechnol.
Biochem. 1995, 59, 1571–1572; (e) Shimotori, Y.; Nakahachi, Y.; Inoue, K.;
Miyakoshi, T. Flavour Frag. J. 2007, 22, 421–429; (f) Cooke, R. C.; van Leeuwen,
K. A.; Capone, D. L.; Gawel, R.; Gordon, G. M.; Mark, A. J. Agric. Food Chem. 2009,
57, 2462–2467; (g) Habel, A.; Boland, W. Org. Biomol. Chem. 2008, 6, 1601–
1604; (h) Shimotori, Y.; Aoyama, M.; Miyakoshi, T. Synth. Commun. 2012, 42,
694–704.
d = 0.92 (t, J = 7.5 Hz, 3H), 1.18–1.72 (m, 10H), 1.45 (s, 9H), 2.67–
2.81 (m, 1H), 3.96 (d, J = 12.5 Hz, 1H), 4.20 (br s, 1H); 13C NMR
(75 MHz, CDCl3) d = 14.1, 19.0, 19.5, 25.7, 28.5, 31.9, 38.6, 50.1,
78.9, 155.2; HRMS (ESI) m/z 250.1784 (250.1783 Calcd for
C
13H25NO2Na, [M+Na]+).
Under an argon atmosphere, to a solution of (S)-14 (36.3 mg,
0.160 mmol) in anhydrous MeOH (2 mL) was added 4 M HCl (diox-
ane solution, 0.16 mL, 0.64 mmol) at 0 °C, and the mixture was stir-
red for 0.5 h at room temperature. After the addition of 4 M HCl
(dioxane solution, 0.84 mL, 3.36 mmol) at 0 °C, the mixture was
stirred for 1.5 h at room temperature. After the mixture was con-
centrated under reduced pressure, the residue was re-precipitated
15. (a) Jurriens, G.; Oele, J. M. J. Am. Oil Chem. Soc. 1965, 42, 857–861; (b) Willhalm,
P. B.; Palluy, E.; Winter, M. Helv. Chim. Acta 1966, 49, 65–67; (c) Tang, C.-S.;
Jennings, W. G. J. Agric. Food Chem. 1968, 16, 252–254.
16. Mosandl, A.; Guenther, C. J. Agric. Food Chem. 1989, 37, 413–418.
17. Schneider, M. J. In Alkaloids: Chemical and Biological Perspectivities; Pelletier, S.
W., Ed.; Pergamon Press: New York, 1996; Vol. 10, pp 155–299.
18. (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813; (b) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–5989.
19. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105,
7754–7755.
from hexane-CHCl3 to afford (S)-2 as a white solid; ½a D20
¼ þ5:7 (c
ꢀ
1.12, EtOH); IR (KBr) 3429, 2955, 2789, 1593, 1456, 1035,
1011 cmꢁ1 1H NMR (500 MHz, CDCl3) d = 0.95 (t, J = 7.0 Hz, 3H),
;
20. For recent synthetic studies of an optically active coniine 2, see: (a) Lebrun, S.;
Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473–2476; (b)
Castro, A.; Ramirez, J.; Juarez, J.; Teran, J. L.; Orea, L.; Galindo, A.; Gnecco, D.
Heterocycles 2007, 71, 2699–2708; (c) Lauzon, S.; Tremblay, F.; Gagnon, D.;
Godbout, C.; Chabot, C.; Mercier-Shanks, C.; Perreault, S.; DeSeve, H.; Spino, C. J.
Org. Chem. 2008, 73, 6239–6250; (d) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org.
Chem. 2009, 74, 144–253; (e) Nomura, H.; Richards, C. J. Org. Lett. 2009, 11,
2892–2895; (f) Kondekar, N. B.; Kumar, P. Synthesis 2010, 3105–3112; (g) Coia,
N.; Mokhtari, N.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2011, 13, 6292–6295.
21. Martinalli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Kosmrlj, B. J. Am.
Chem. Soc. 2002, 124, 3578–3585.
22. Chen, C.-S.; Fujimoto, Y.; Grdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.
23. van Assema, S. G. A.; Tazelaar, C. G. J.; de Jong, G. B.; van Maarseveen, J. H.;
Schakel, M.; Lutz, M.; Spek, A. L.; Slootweg, J. C.; Lammertsma, K.
Organometallics 2008, 27, 3210–3215.
1.36–1.54 (m, 3H), 1.58–2.04 (m, 7H), 2.74–2.88 (m, 1H), 2.88–
3.01 (m, 1H), 3.36–3.53 (m, 1H), 9.19 (br s, 1H), 9.48 (br s, 1H);
13C NMR (125 MHz, CDCl3) d = 13.7, 18.5, 22.2, 22.4, 28.1, 35.3,
44.7, 57.1; HRMS (ESI) m/z 128.1439 (128.1439 Calcd for
C8H18NNa, [M+H]+).
Acknowledgments
We thank the Collaborative Research Center of Meisei Univer-
sity for NMR analysis and Mr. Syozo Akiya (Meisei University) for
helpful discussions.
References
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